Fibroblast growth factors are polypeptides expressed in developing and adult tissues. They are involved in several physiological mechanisms including for example metabolic regulation and cellular differentiation. A whole family of more than twenty fibroblast growth factors exists (the FGF family). Three members of the FGF family including FGF19, FGF21, and FGF23 form a subfamily functioning as endocrine factors involved in metabolic regulation.
Fibroblast Growth Factor 21 or FGF-21, herein for short FGF21, is expressed preferentially in the liver and has been shown to exert hormone-like metabolic effects.
For example, FGF21 has been demonstrated to activate glucose uptake in mouse adipocytes, to protect mice from diet induced obesity when over-expressed in transgenic mice, and to lower blood glucose and triglyceride levels when administered to diabetic rodents (Kharitonenkov et al., J. Clin. Invest. (2005), 115:1627-1635).
The lowering effect of FGF21 on blood glucose and triglycerides has also been shown in diabetic monkeys. FGF21 was also able to decrease LDL and to increase HDL significantly in diabetic monkeys (Kharitonenkov et al., Endocrinology (2007), 148(2):774-81).
In diet induced obese mice and ob/ob mice, FGF21 was furthermore shown to lower body weight, predominantly by an increase in energy expenditure and a reduction in adiposity (Coskun et al., Endocrinology (2008), 149(12): 6018-6027).
Based on these results FGF21 has been suggested as a pharmacological agent with the potential to treat diabetes, dyslipidemia, obesity, cardiovascular diseases, and metabolic syndrome. Metabolic syndrome includes aspects like insulin resistance, dyslipidemia, visceral obesity and hypertension, see e.g. the definition of metabolic syndrome in Grundy et al., Circulation (2004), (109): 433-438.
FGF21 may furthermore be used as a pharmacological agent with a potential to treat Non Alcoholic Fatty Liver Disease (NAFLD), see Coskun et al. Endocrinology, 2008 cited above, and Xu et al., Diabetes (2009, 58(1):250-9, published electronically 7 Oct. 2008 ahead of print). NAFLD has been defined by Erickson, J. Lipid Res. (2008), published electronically 12 Dec. 2008 ahead of print.
Yie et al. studied the role of the N- and C-termini of FGF21 in receptor interaction and activation, see FEBS Letters, 583 (2009), 19-24.
WO 2003/011213 A2 discloses a method for treating diabetes of type 1 and 2, or obesity, by use of FGF21 compounds with at least 95% identity to the FGF21 precursor amino acid sequence.
WO 2003/061712 A1 discloses muteins of FGF21 with improved pharmaceutical properties, e.g. A145E.
WO 2005/091944 A2 discloses PEGylated derivatives of FGF21, FGF21-K59C, and FGF21-K122C.
WO 2005/113606 A2 discloses various FGF21 fusion proteins with the Fc portion of an IgG4 immunoglobulin, or human serum albumin.
WO 2006/028595 A2 discloses further muteins of FGF21 with reduced capacity of O-glycosylation when expressed in yeast, e.g. L118C-A134C-S167A.
WO 2006/028714 A1 discloses additional muteins of FGF21 with reduced susceptibility for proteolytic degradation when expressed in yeast, e.g. L153I.
WO 2006/065582 A2 discloses still further muteins of FGF21 with reduced deamidation, e.g. des-HPIP-L118C-A134C-N121D.
WO 2006/078463 A2 discloses a method for treating cardiovascular disease by use of native mature FGF21 or specified variants thereof.
WO 2008/121563 discloses FGF21 polypeptides modified to include non-naturally encoded amino acids, as well as derivatives thereof.